Gene Therapy for Metastatic Melanoma
Overview Amgen has used a recombinant herpes simplex virus 1 (HSV1) which encodes human cytokine granulocyte-macrophage colony stimulating factor (GM-CSF), which infects and replicates in tumor cells, causing the cells to lyse and stimulating a cytotoxic T-cell response against tumor cells.http://www.biotechnologyevents.com/node/3673 The virus's technical name is Talimogene laherparepvec, referred to as T-VEC. Creation of the Virus Genetic modifications were made to the HSV1 virus to attenuate (inactivate the herpes component) of the virus, increase the selectivity for cancer cells, and secrete the cytokine GM-CSF, which initiates an immune response. In order to improve the tumor killing efficiency, the JS1 strain of HSV1 was used. The ICP34.5 and ICP47 segments were deleted from the virus, preventing the infection of non-tumor cells and enabling antigen presentation. The US11 fragment was moved in the viral genome to increase replication and oncolysis of tumor cells. A human GM-CSF gene was inserted to enhance anti-tumor response. The GM-CSF gene works to increase the anti-tumor response by recruiting dendritic cells to the tumor site.[http://en.wikipedia.org/wiki/Talimogene_laherparepvec Talimogene laherparepvec] (n.d.). In Wikipedia. Retrieved on 12 December 2013 from http://en.wikipedia.org/wiki/Talimogene_laherparepvec Effects T-VEC functions in two ways: it destroys cancer cells directly, and recruits immune cells to destroy the cancer cells. The immune response causes the immune system to attack cancer cells in other tumors in the body, including those which are not directly affected by the virus. The virus directly destroys cancer cells by attracting dendritic cells, which bind to the surface of the cell and present antigens for T-cells to recognize. Ultimately, this causes a cytotoxic T-cell to destroy the cancer cell.BL Liu, M Robinson, Z-Q Han, RH Branston, C English, P Reay, Y McGrath, SK Thomas, M Thornton, P Bullock, CA Love and RS Coffin (2003). [http://www.phys.mcw.edu/documents/PDF/Research%20Papers/Liu.pdf ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties]. Gene Therapy 10, 292-303. Clinical Trial Progress A phase II clinical trial has demonstrated a response rate of 26% and an overall one year survival of 54% and a two year survival of 52%.Senzer NN, Kaufman HL, Amatruda T, et al. [http://jco.ascopubs.org/content/27/34/5763.long Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor–encoding, second-generation oncolytic herpesvirus in patents with unresectable metastatic melanoma]. J Clin Oncol. 2009;27:5763-5771. One phase III trial has been performed, indicating a response rate of 16% of patients with the treatment compared to a 2% response in the control group.Andtbacka RHI, Collichio FA, Amatruda T et al. [http://meetinglibrary.asco.org/content/117592-132 OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma]. J Clin Oncol 31, 2013 (suppl; abstr LBA9008). A phase II clinical trial has demonstrated efficacy in squamous cell head and neck cancers. Study of Safety and Efficacy of OncoVEXGM-CSF With Cisplatin for Treatment of Locally Advanced Head and Neck Cancer (2011). ClinicalTrials.gov. Retrieved on 12 December 2013 from http://www.clinicaltrials.gov/ct2/show/NCT01161498 Phase I studies are ongoing for patients with pancreatic, breast, and colorectal cancers. Chang KJ, Senzer NN, Binmoeller K, Goldsweig H, Coffin R. [http://meetinglibrary.asco.org/content/96667-114 Phase I dose-escalation study of talimogene laherparepvec (T-VEC) for advanced pancreatic cancer] (ca). J Clin Oncol. 2012;30(suppl; abstr e14546).Hu JCC, Coffin RS, Davis CJ, et al. [http://clincancerres.aacrjournals.org/content/12/22/6737.full.pdf A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor]. Clin Cancer Res. 2006;12:6737-6747. References